In situ forming systems have been reported in the literature for various biomedical applications, including drug delivery and tissue culture treatment, over the past few years (see R. L. Dunn et al., Biodegradable in-situ forming implants and methods of producing the same, US Patent 4 (1990) 938-763; B. O. Haglund et al., J. Control. Release 41 (1996) 29-235; and Y. An et al., J. Control. Release 64 (2000) 205-215).
There are several possible mechanisms that lead to in situ gel formation: solvent exchange, pH change, ultraviolet (UV) irradiation, ionic cross-linkage, and temperature modulation. Negative thermosensitive polymers having a lower critical solution temperature (LCST)) and thermoreversible hydrogels undergoing a reversible sol-gel transition upon heating or cooling are the most commonly investigated materials in stimuli-sensitive polymer systems for drug delivery.
Some synthetic polymers were reported to exhibit thermoreversible gelation behavior at body temperature and were used for drug delivery, but their inherent problems associated with biocompatibility and biodegradability still remain unsolved.
In this connection, Korean Patent No. 10-0813224 issued to the present inventors discloses a protein drug delivery system based on high molecular weight methyl cellulose as a natural polymer and coacervates.
Many technologies for drug delivery are known. Such technologies are, for example, drug delivery technologies using polymers, drug delivery technologies using protein drugs, drug delivery systems using PLGA-PEG-PLGA-based synthetic polymers, and drug delivery systems using gel depots.
However, these technologies suffer from several problems, including insufficient biocompatibility of the synthetic polymers, residual toxic chemicals, and complicated processes. Other challenges related to the synthetic polymers have higher gelling temperatures compared to body temperature and reduced elimination efficiency due to their high molecular weights, and the time-controlled release of drugs is difficult to obtain. Furthermore, the synthetic polymers tend to lose their gel shape by dilution in the presence of excessive body fluids. The addition of toxic salting-out salts may cause poor biocompatibility.
Thus, there is an urgent need to develop a new drug delivery system that is free from associated with biocompatibility and biodegradability of polymers, increases the stability of a drug, enables a single dosage of a drug intended for long-term administration, and is injected into a tissue around a target to deliver a drug to the target with high efficiency.
As a result of repeated research, the present inventors have found that gelation of low molecular weight methyl cellulose alone as a natural polymer without a salting-out salt at body temperature enables the production of an effective thermosensitive gel for parenteral drug delivery. The present invention has been achieved based on this finding.